Immune cells help attack and eliminate foreign invaders such as infectious agents. However, in certain instances, such as in autoimmune disorders, allergies, and the rejection of tissue or organ transplants, the immune system can be the cause of illness. In transplantation of a graft (e.g., a cell, a tissue, or an organ) from a donor to a recipient, the recipient's immune reaction to the graft causes illness. Nevertheless, transplantation of cells, tissues and organs is very common and is often a life-saving procedure. Organ transplantation is the preferred treatment for most patients with chronic organ failure. Despite great improvement in treatments to inhibit immune rejection of a transplant (i.e., graft rejection), this rejection—which includes both acute and chronic rejection—continues to be the single largest impediment to successful organ transplantation. One-year survival rates for renal transplants, for example, average 88.3% with kidneys from deceased donors and 94.4% with kidneys received from living donors. The corresponding five-year survival rates for the transplanted kidneys are 63.3% and 76.5% (OPTN/SRTR Annual Report, 2002. Chapter 1 of the Annual Report produced by the Scientific Registry of Transplant Recipients (SRTR) in collaboration with the Organ Procurement and Transplantation Network (OPTN). See world wide web at unos.org/data/ar2002/ar02_chapter_one.htm.). For liver transplants, the one-year survival rates are 80.2% and 76.5% for livers from deceased and living donors, respectively. The corresponding five-year liver graft survival rates are 63.5% and 73.0% (OPTN/SRTR Annual Report, 2002. Chapter 1 of the Annual Report produced by the Scientific Registry of Transplant Recipients (SRTR) in collaboration with the Organ Procurement and Transplantation Network (OPTN). See world wide web at unos.org/data/ar2002/ar02_chapter_one.htm). The use of immunosuppressant drugs, especially cyclosporine A and more recently tacrolimus, has dramatically improved the success rate of organ transplantation. These agents have especially been successful in inhibiting acute rejection. Yet, as the numbers above show, there is still a need to improve both the short-term and especially the long-term survival rates following transplantation.
There are multiple types of transplants. A graft transplanted from one individual to the same individual is called an autologous graft or autograft. A graft transplanted between two genetically identical or syngeneic individuals is called a syngeneic graft. A graft transplanted between two genetically different individuals of the same species is called an allogeneic graft or allograft, and a graft transplanted between individuals of different species is called a xenogeneic graft or xenograft.
Currently more than 40,000 kidney, heart, lung, liver and pancreas transplants are performed in the United States each year (Abbas et al., 2000; Cellular and Molecular Immunology (4th edition), p. 363-383 (W.B. Saunders Company, New York). Other possible transplants include, but are not limited to, vascular tissue, eye, cornea, lens, skin, bone marrow, muscle, connective tissue, gastrointestinal tissue, nervous tissue, bone, stem cells, islets, cartilage, hepatocytes, and hematopoietic cells. Unfortunately, there are many more candidates for a transplant than there are donors. To overcome this shortage, a major effort is being made to learn how to use xenografts. While progress is being made in this field, at present most transplants are allografts.
In transplantation, therefore, the donor's genetic background is often different from the genetic background of the recipient (e.g., allotransplantation), and the donor and recipient thus differ in their histocompatibility antigens, i.e., antigens of the major histocompatibility complex (MHC), called the HLA system in humans. The recipient therefore recognizes the graft as a foreign substance, and various immune responses work to reject and eliminate the graft. Graft rejection refers to the immune responses of the recipient against the graft. The immune responses that act in graft rejection can be classified into (1) hyper-acute rejection, which is a strong rejection occurring immediately after transplantation; (2) acute rejection, which is observed within a few months after transplantation (also included is acute vascular rejection such as accelerated humoral rejection and de novo acute humoral rejection); and (3) chronic rejection observed several months after transplantation. Rejection is normally a result of T-cell mediated and/or humoral antibody attack, but may include additional secondary factors, cytokines and other immune cells such as macrophages. The molecules that the recipient's immune cells recognize as foreign on allografts are called alloantigens and these molecules on xenografts are called xenoantigens. The recipient's lymphocytes or antibodies that react with alloantigens or xenoantigens are described as being alloreactive or xenoreactive, respectively.
Cellular immunity (due to immunocompetent cells represented by T cells) and humoral immunity (due to antibodies) work in an intricately coordinated manner in graft rejection (see Rocha et al. 2003 Immunol. Rev. 196: 51-64). T cell responses to antigens from the donor organ are generally acknowledged to mediate acute rejection. In allotransplantation, CD8+ cytotoxic T cells recognize donor MHC molecules expressed on the allograft and/or on leukocytes (i.e., antigen-presenting cells) within the graft. In cases in which the allograft differs from the recipient at both class I and class II sites, recognition of the MHC molecules leads to activation of both CD8+ and CD4+ T cells. While allogeneic MHC antigens provide one signal to stimulate CD4+/T helper cells of the recipient, recipient macrophages provide a second signal, interleukin 1 (IL-1), which is essential to the activation of T helper cells. Activated T helper cells produce IL-2, which leads to the proliferation of cytotoxic T cells and lymphokine-activated killer cells and the release of IL-4 and IL-6. In addition, IL-2 promotes release of interferon gamma as well as tumor necrosis factor and other proinflammatory cytokines.
APCs (antigen-presenting cells, e.g., dendritic cells) are also involved in graft rejection, as mentioned above. Allograft and xenograft antigens can be processed and presented indirectly by recipient APCs, which may infiltrate the graft. Recipient APCs presenting donor antigens are transported to lymph nodes through the circulation, where they activate T cells. APC activity leads to lymphocyte proliferation and eventual T cell infiltration into the donor graft.
Another immune response in graft rejection is the production of anti-donor antibodies (such as alloantibodies in the case of an allograft), which is mediated by B-cells. This response, however, requires the activity of CD4+ T cells that stimulate B-cell growth, differentiation, and secretion of antibodies. Binding of alloantibodies to MHC antigens expressed on endothelial cells activates a complex response involving the complement and coagulation pathways, which ultimately results in inflammation and graft injury. Alloantibodies can also mediate antibody-dependent cellular cytotoxicity (ADCC) via the Fc region of the antibody molecule. The activities of alloantibodies and complement may be important for hyperacute, acute humoral, and chronic rejection of a graft, and alloantibodies to donor HLA class I or class II antigens have been associated with chronic rejection of various transplanted organs.
As a result of graft rejection, the graft ultimately becomes necrotic. Furthermore, the recipient develops not only severe systemic symptoms such as fever, leukocytosis and fatigue, but also swelling and tenderness at the transplantation site. Severe complications such as infections may also occur.
A limited number of immunosuppressive agents that suppress the function of immunocompetent cells are used to suppress graft rejection. Such immunosuppressive agents include cyclosporine (CsA); tacrolimus (FK-506); azathioprine (AZ); mycophenolate mofetil (MMF); mizoribine (MZ); leflunomide (LEF); adrenocortical steroids (also known as adrenocortical hormones, corticosteroids, corticoids) such as prednisolone and methylprednisolone; sirolimus (also known as rapamycin); deoxyspergualin (DSG); and FTY720 (also called Fingolimod, chemical name: 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride). Also being clinically developed as immunosuppressive agents are agents that block CTLA-4 and CD28, which are molecules responsible for transducing costimulatory signals necessary for the activation of T cells (costimulatory signal transduction molecules); such agents include CTLA-4 drugs that use the soluble region of CTLA-4 and the gene encoding it.
General immunosuppressives, such as corticosteroids and cytokine antagonists, can elicit undesirable side effects including toxicity and reduced resistance to infection. Thus, alternative, and perhaps more specific, methods of treating autoimmunity and promoting graft survival are needed.
One molecule that has been thought to induce immunosuppression and promote graft survival is OX-2, or CD200. CD200 is expressed on the surface of B cells, some T cells, dendritic cells and other cells and possesses a high degree of homology to molecules of the immunoglobulin gene family. CD200 has been implicated in immune suppression, and it has been shown, for example, that CD200-expressing cells can inhibit the stimulation of Th1 cytokine production (Gorczynski et al., 1998 Transplantation 65:1106-1114). In addition, soluble CD200 has been shown to promote allo- and xenograft survival in mice and to decrease antibody response to sheep erythrocytes in mice (Gorczynski et al. 1999 J. Immunol. 163: 1654-1660). Further, CD200-knockout mice exhibit a decreased ability to down-regulate APC activation compared to wildtype mice, resulting in chronic inflammation in the central nervous system, a hyper-inflammatory response, and increased susceptibility to certain experimental autoimmune disorders (Hoek et al. 2000 Science 290: 1768-1771). The immunosuppressive effects of CD200 are believed to be the result of CD200 binding to its receptor, CD200R (Hoek et al. supra; Gorczynski et al. 2000 J. Immunol. 165: 4854), which is expressed on cells of monocyte/myeloid lineage and of T-lymphocyte origin.
While CD200 has been shown to elicit immunosuppressive effects, an antibody to CD200 has been shown to inhibit these immunosuppressive effects. For example, an anti-CD200 antibody (including an anti-CD200 F(ab′)2 fragment) abolished the CD200Fc-induced prolonged survival of rat islet xenografts in mice (Gorczynski et al. 2002 Transplantation. 73: 1948-53).
Contrary to the published reports discussed above, the present disclosure demonstrates that an anti-CD200 antibody and compositions comprising an anti-CD200 antibody promote graft survival. Accordingly, the present disclosure provides novel compositions and methods for inhibiting graft rejection and promoting graft survival.